The principle of TIPS is that a homogeneous solution of polymer–solvent or
polymer–solvent–non-solvent at elevated temperatures is quenched to a lower
temperature by cooling to induce the uniform solution into polymer-rich and
polymer-lean phases. After demixing is induced, the solvent is removed by extraction,
evaporation, or freeze-drying, and pores form in the scaffold due to the
removal of the solvent.50 There are two mechanisms of phase separation: solid–
liquid (S–L) phase separation and liquid–liquid (L–L) phase separation. The typical
schematic representation of the temperature–concentration phase diagram for
a binary polymer–solvent system with an upper critical solution temperature for
TIPS is shown in Figure 4. The solid binodal curve represents the thermodynamic
equilibrium of L–L demixing, which is often used to approximate the cloud point at
which the clear solution becomes turbid. In the L–L demixing region, a polymerrich
phase and a polymer-lean phase co-exist.51,52 Meanwhile on the dashed spinodal
curve, the second derivative of the Gibbs free energy of mixing is equal to
zero. The area between the binodal and spinodal curves is the metastable region
where the polymer concentration is lower or higher than the concentration at the
critical point, while the area below the spinodal curve is the unstable region. L–L
demixing located in the metastable region leads to bead-like or poorly connected
closed pores for polymer concentrations lower or higher than the critical point,
respectively.53,54 When L–L demixing is in the unstable region, an open porous and
well-interconnected structure can be obtained.55 If the temperature of the solution
is decreased to or beyond the freezing point of the solvent prior L–L phase seperation,
S–L phase separation induced by the solidification of the solvent occurs and
the anisotropic ladder-like structure with relatively small pores forms.